Is ERCC6 p.Arg767Cys (c.2299C>T) pathogenic?

ERCC6 p.Arg767Cys (c.2299C>T) is classified Uncertain significance in ERCC6 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-10-22). AlphaMissense: likely benign (0.1452); Ultra-rare (popmax 0.0234%, nfe).

How common is ERCC6 p.Arg767Cys (c.2299C>T) in the general population?

ERCC6 p.Arg767Cys (c.2299C>T) is ultra-rare (popmax 0.0234%, nfe) (gnomAD).

What do computational predictors say about ERCC6 p.Arg767Cys (c.2299C>T)?

AlphaMissense predicts likely benign (score 0.1452) — an in-silico prediction, not a clinical call.

ERCC6 p.Arg767Cys

c.2299C>T · rs370105701 · VCV2077832

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1452 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0234%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1452	likely benign
REVEL	0.818	moderately pathogenic-leaning
SaProt	LLR -11.28	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	Δ0.36	acceptor gain, 10 bp away · masked 0 · deltas
Pangolin	Δ0.45	gain · loss 0.21 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 12	GERP 1.5, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 74 kb · p 0.017 · regional, not allelic
Overall
CADD	35.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0234% European (non-Finnish) · 276/1,178,680 alleles

Filtering AF 0.0211% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0202%

Overall 0.0179% 289/1,611,992 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0234%	4,271
South Asian	0.0066%	15,163
African / African-American	0.00402%	24,891
Remaining individualsnot grpmax-eligible	0.0032%	31,214
Finnishnot grpmax-eligible	0.00313%	31,919

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: ERCC6
Protein: p.Arg767Cys
Coding: c.2299C>T
MANE Select: NM_000124
dbSNP: rs370105701
Type: single nucleotide variant
Location: chr10:49476298 (GRCh38)
Gene constraint: LOEUF 0.803 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.12 · 12 PDB
Residue 767: an α-helix

Full ERCC6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ERCC6 p.Arg767His Uncertain significance ★★ ⚠ same residue
ERCC6 c.1397+1G>C Likely pathogenic ★★ same type
ERCC6 c.1526+1G>T Pathogenic/Likely pathogenic ★★ same type
ERCC6 c.2169+1G>A Likely pathogenic ★★ same type
ERCC6 c.2170-1G>A Pathogenic/Likely pathogenic ★★ same type
ERCC6 c.2286+1G>A Pathogenic/Likely pathogenic ★★ same type
ERCC6 c.2287-2A>G Pathogenic/Likely pathogenic ★★ same type
ERCC6 c.2599-26A>G Pathogenic/Likely pathogenic ★★ same type

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/ercc6-p-arg767cys (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown